Sampling phasic dopamine signaling with fast-scan cyclic voltammetry in awake, behaving rats.

Fast-scan cyclic voltammetry (FSCV) is an electrochemical technique that permits the in vivo measurement of extracellular fluctuations in multiple chemical species. The technique is frequently utilized to sample sub-second (phasic) concentration changes of the neurotransmitter dopamine in awake and behaving rats. Phasic dopamine signaling is implicated in reinforcement, goal-directed behavior, and locomotion, and FSCV has been used to investigate how rapid changes in striatal dopamine concentration contribute to these and other behaviors. This unit describes the instrumentation and construction, implantation, and use of components required to sample and analyze dopamine concentration changes in awake rats with FSCV.

Amphetamine paradoxically augments exocytotic dopamine release and phasic dopamine signals.

Drugs of abuse hijack brain-reward circuitry during the addiction process by augmenting action potential-dependent phasic dopamine release events associated with learning and goal-directed behavior. One prominent exception to this notion would appear to be amphetamine (AMPH) and related analogs, which are proposed instead to disrupt normal patterns of dopamine neurotransmission by depleting vesicular stores and promoting nonexocytotic dopamine efflux via reverse transport. This mechanism of AMPH action, though, is inconsistent with its therapeutic effects and addictive properties, which are thought to be reliant on phasic dopamine signaling. Here we used fast-scan cyclic voltammetry in freely moving rats to interrogate principal neurochemical responses to AMPH in the striatum and relate these changes to behavior. First, we showed that AMPH dose-dependently enhanced evoked dopamine responses to phasic-like current pulse trains for up to 2 h. Modeling the data revealed that AMPH inhibited dopamine uptake but also unexpectedly potentiated vesicular dopamine release. Second, we found that AMPH increased the amplitude, duration, and frequency of spontaneous dopamine transients, the naturally occurring, nonelectrically evoked, phasic increases in extracellular dopamine. Finally, using an operant sugar reward paradigm, we showed that low-dose AMPH augmented dopamine transients elicited by sugar-predictive cues. However, operant behavior failed at high-dose AMPH, which was due to phasic dopamine hyperactivity and the decoupling of dopamine transients from the reward predictive cue. These findings identify upregulation of exocytotic dopamine release as a key AMPH action in behaving animals and support a unified mechanism of abused drugs to activate phasic dopamine signaling.

[Peritoneal carcinomatosis of colorectal origin: results of cytoreductive surgery with peritonectomy and hyperthermic intraoperative chemotherapy]. / Peritonealkarzinose kolorektalen Ursprungs : Ergebnisse der zytoreduktiven Chirurgie mit Peritonektomie und hyperthermer intraoperativer Chemotherapie.

Until recently peritoneal carcinomatosis (PC) arising from colorectal cancer (CRC) was considered to be a terminal disease manifestation. Despite palliative systemic chemotherapy (CHT) the majority of patients died within a few months. Nowadays cytoreductive surgery (CRS) of the peritoneal cavity in combination with hyperthermic intraperitoneal CHT and perioperative systemic CHT may offer a chance for long-term survival in selected groups of patients. In this study we report the results obtained with this treatment strategy in 30 consecutive patients. Data were assessed prospectively. After a median follow-up of 16.9 months the median survival time in all 30 patients reached 24.3 months. Favorable prognostic factors are a low extent of intraperitoneal metastases as characterized by a low peritoneal cancer index (median survival PCI ≤ 10: 33.2 months vs. PCI 11-19: 12.1 months) and a complete or nearly complete CRS (median survival CCR 0/1: 33.1 months vs. CCR2/3: 12.1 months). The 2-year overall survival was 89% for patients with a PCI ≤ 10 and 65% for those with surgical CCR 0/1 cytoreduction. As not every patient with CRC and PC may profit from this relatively aggressive therapy an interdisciplinary patient selection (tumor board) and treatment in experienced surgical oncology centers is recommended.

Intraperitoneal chemotherapy with mitoxantrone in malignant ascites.

A retrospective analysis of intraperitoneal mitoxantrone instillation therapy for malignant ascites in advanced breast and gynecologic pelvic cancers was performed to confirm the efficacy and safety of this therapy. Several smaller phase II trials had suggested good palliative effects. In 143 patients (37 breast cancer and 106 gynecologic cancers), 257 instillations were registered. Response in breast cancer was induced in 49% and in 63% with gynecologic cancer. Severe or life-threatening clinical or laboratory side effects related to intraperitoneal mitoxantrone occurred in 2.7% (clinical) or 1.9% (laboratory) of the 257 instillations. Induction of adverse side effect was dose dependent. Intraperitoneal chemotherapy with mitoxantrone for treatment of malignant ascites in breast cancer and gynecologic malignancy is effective and well tolerated. For this treatment 30 mg mitoxantrone in > or = 1000 mL carrier solution (e.g., saline) is recommended. A minimal concentration of at least 10 micrograms/mL should be achieved.

Dopamine mediation of the feeding response to violations of spatial and temporal expectancies.

The present studies were aimed at further characterizing the role of DA in motivation. Rats, conditioned to expect food in one environment and no food in another, all received food on the test night. Those in the environment in which food was unexpected ate four times as much as those eating where food was expected. The overeating was eliminated by administration of the D2 antagonist raclopride. Another expectancy, timing of light offset in rats entrained to a fixed light--dark cycle, was violated by unexpectedly turning the lights off 1 h early. This provoked an elevation in food intake, which was also eliminated by the administration of raclopride. Feeding in two other situations not involving violation of expectancies (food deprivation; normal light offset) was unaffected by DA antagonism. These findings support the idea that DA signals errors in expectancy and that DA signaling is necessary for certain behavioral responses to unexpected events.

[Introduction of routine hepatitis A immunization in Israel--the first in the world].

Notification of hepatitis A, which is endemic in Israel, has been compulsory since the establishment of the State. From 1992-98 an average of 2,600 cases were reported annually. Many infections are asymptomatic and mild, especially in children. In general, severity increases with age; in Western countries the case fatality rate is 1.5/1,000 among children less than 5 years old and 27/1,000 among those over 50. Until 1987 incidence in Israel was higher in Jews than in non-Jews, but since 1988 incidence has been about 50% higher in non-Jews. Among Jews highest age specific rates shifted from children 1-4 years old to children 5-9 years old in 1970, and in non-Jews in 1989. Improved sanitary conditions and personal hygiene have reduced very early childhood exposure and hence increased the proportion of susceptible older children and adults, in whom symptomatic disease is more prevalent. Israel is the first country in the world to include hepatitis A vaccine in its routine immunization schedule. The vaccine is given in 2 doses: at 18 months and 24-30 months of age, and there will be epidemiologic and serologic follow-up. A significant decrease in hepatitis A morbidity is expected in small children within 5 years. The percentage of reported cases in older children and in adults is expected to increase, although the absolute incidence among these groups will decrease.

Food deprivation does not potentiate glucose taste reactivity responses of chronic decerebrate rats.

The chronic supracollicular decerebrate (CD) rat fails to increase meal size in response to systemic/metabolic aspects of food deprivation. Here we asked whether or not deprivation increases immediate oral motor responding to taste stimuli (taste reactivity) in CD rats, as it does in neurologically intact controls. The responses of CD rats were evaluated as functions of glucose concentration and deprivation state, with taste reactivity responses recorded myographically during 15-s intraoral infusions and during 45-s post-infusion periods. Five glucose concentrations (0, 3.2, 6. 25, 12.5, 25%) were each presented three times during each test session. The rats were tested when not-deprived (i.e. receiving their full complement of gavage feedings), deprived (23.5 h) of food and water, and deprived of food but not water. The number of oral motor responses emitted increased monotonically with stimulus concentration; during oral infusions the increase was greatest over the lower half of the concentration range, whereas responding increased linearly with concentration in the post-infusion period. This CD response profile resembled that obtained previously with neurologically intact rats tested according to the same protocols. In contrast to results obtained in intact rats, deprivation did not influence the CD's response to glucose at any concentration or for any observation period. Although the caudal brainstem may receive and process information associated with deprivation state, neural interactions between forebrain and brainstem structures appear necessary for the behavioral expression of deprivation effects on meal size or, as we can now conclude, on immediate oral motor responses to taste stimuli.

Neurotransmitter transporters: target for endocrine regulation.

Aminergic signaling in the CNS is terminated by clearance from the synapse via high-affinity transporter molecules in the presynaptic membrane. Relatively recent sequence identification of these molecules has now permitted the initiation of studies of regulation of transporter function at the cellular and systems levels. In vitro studies provide evidence that the transporters for dopamine, serotonin, and gamma-aminobutyric acid are substrates for regulation by protein kinase C signaling. In vivo studies provide evidence that insulin and adrenal and gonadal steroid hormones may regulate the synthesis and activity of the transporters. Future directions should permit evaluation of the role of endocrine regulation in neurotransmitter clearance, and thus in the maintenance of normal CNS aminergic signaling.

Amiloride-sensitive sodium signals and salt appetite: multiple gustatory pathways.

In the rat, the ionic specificity of Na+ appetite is thought to rely on amiloride-sensitive Na+ signals conveyed by the chorda tympani (CT) nerve. We evaluated whether robust Na+ appetite relies exclusively on CT-mediated amiloride-sensitive Na+ signals. Amiloride dramatically reduced sham drinking of NaCl (41.9 +/- 9.0 vs. 6.9 +/- 3.7 ml, 0.1 M NaCl without vs. with 100 microM amiloride), which resulted in intake that was not different from intake of a non-Na+ salt solution (8.8 +/- 2.3 ml, 0.15 M KCl). In addition, intake of 0.1 M NaCl in CT-transected (CTX) rats was reduced (35.8 +/- 13.3 vs. 8.67 +/- 3.4 ml, sham-operated vs. CTX rats), but the addition of amiloride (100 microM) further reduced intake in CTX rats (0.5 +/- 0.29 ml). These data support the idea that amiloride-sensitive Na+ channels are the critical gustatory substrate for Na+ identification during Na+ appetite in the rat. However, the data indicate that these amiloride-sensitive signals are not conveyed exclusively by the CT nerve but by an additional afferent pathway.

Sodium depletion and aldosterone decrease dopamine transporter activity in nucleus accumbens but not striatum.

Motivated behaviors, including sodium (Na) appetite, are correlated with increased dopamine (DA) transmission in the nucleus accumbens (NAc). DA transporter (DAT) modulation affects DA transmission and may play a role in motivated behaviors. In vivo Na depletion, which reliably induces Na appetite, was correlated with robust decreases in DA uptake via the DAT in the rat NAc with rotating disk electrode voltammetry [1,277 +/- 162 vs. 575 +/- 89 pmol. s-1. g-1; Vmax of transport for control vs. Na-depleted tissue]. Plasma aldosterone (Aldo) levels increase after in vivo Na depletion and contribute to Na appetite. Decreased DAT activity in the NAc was observed after in vitro Aldo treatment (428 +/- 28 vs. 300 +/- 25 pmol. s-1. g-1). Neither treatment affected DAT activity in the striatum. These results suggest that a direct action of Aldo is one possible mechanism by which Na depletion induces a reduction in DAT activity in the NAc. Reduced DAT activity may play a role in generating increased NAc DA transmission during Na appetite, which may underlie the motivating properties of Na for the Na-depleted rat.

Effectiveness of a nationwide infant immunization program against Haemophilus influenzae b. The Israeli Pediatric Bacteremia and Meningitis Group.

An ongoing nationwide prospective surveillance program for invasive H. influenzae b (Hib) disease in Israel enabled us to study the effectiveness of a national infant Hib immunization program, which included all infants born since January 1994. The vaccine used was Hib polysaccharide conjugated to outer membrane protein complex of Neisseria meningitidis b (PRP-OMPC). For the cohort born during the 3 years since January 1994, the vaccine effectiveness was 94.9% for all invasive Hib diseases and 96.6% for meningitis. The efficacy in fully immunized subjects was 98.7 and 99.5%, respectively. A herd immunity effect could be observed, since a reduction in cases also occurred among infants too young to be immunized. No increase in invasive cases caused by S. pneumoniae and N. meningitidis was observed during the study period. This is the first report outside North America and Western Europe that demonstrates a nationwide extensive reduction of invasive Hib disease within a short time of the introduction of Hib conjugate vaccines to the infant immunization program.

[Importance of variation criteria in statistical evaluation of the immune status of work crews]. / Znachenie variatsionnykh kriteriev pri statisticheskoi otsenke immunnogo statusa professional'nykh kollektivov.

Variation criteria--variation coefficient, Fisher criterion (F-value) and suggested by the authors index of homeostasis--enable to evaluate completely the state of occupational crews and reveal their compensated disadaptation. Administration of adaptogens (such as oxymethacil) is expedient for correction of premorbid conditions in occupational crews. Increased aboriginality and random selection during occupational activities considerably better adaptational characteristics of the occupational crews.

Learned tolerance to ethanol-induced c-Fos expression in rats.

With c-Fos immunoreactivity as a marker for neural activity, we examined whether environmental cues associated with ethanol injection influence the expression of tolerance to ethanol-induced c-Fos activation. Over 24 training days, male Long-Evans rats received ethanol injection (2.5 g/kg) in one environment and saline injection in a different environment. Relative to rats that received ethanol for the first time, ethanol-induced c-Fos expression in the paraventricular nucleus of the hypothalamus (PVN) and the locus coeruleus (LC) was significantly reduced in rats that had received multiple prior ethanol administrations. However, tolerance was partially reversed when ethanol was given in the saline-paired, rather than the ethanol-paired, environment. Results suggest that tolerance to ethanol, as indexed by c-Fos expression in the PVN and the LC, is mediated in part by Pavlovian conditioned responses to cues that predict ethanol administration.

Reward comparison in chronic decerebrate rats.

The simultaneous contrast paradigm was used to evaluate responsiveness to a low (0.05 M) and a high (0.5 M) concentration of sucrose under two conditions in intact and chronic decerebrate rats. In one condition the low concentration was presented on one day and the high concentration on another. In the other condition presentation of the two concentration was alternated within the same daily session. In each case there was a total of 40 trials/day during which the stimulus was delivered intraorally for 2 s at a rate of 1.5 ml/min with a 30-s intertrial interval. The results showed that the intact rats always licked more for the high than for the low concentration of sucrose but that the magnitude of the effect was larger when given the opportunity to compare the two concentrations within the same daily session. The decerebrate rats produced a similar pattern, but the concentration effect was evident only when the stimuli were alternated within the same daily session. These data stand as the first evidence that the isolated caudal brain stem is adequate for the expression of a behavior that depends on comparison processes involving short-term memory.

Dopamine and sodium appetite: antagonists suppress sham drinking of NaCl solutions in the rat.

Sodium (Na) ingestion in rats depleted of Na is a strong, motivated behavior that is enhanced further when depleted rats are sham drinking. Dopamine plays a critical role in motivation, including reward associated with consumption of palatable tastes. The present studies assessed the role of dopamine in real and sham drinking of NaCl solutions after Na depletion with the diuretic furosemide (10 mg/kg). Dopamine (D2) receptor antagonists were evaluated (Haloperidol [0.1 mg/kg] and raclopride [0.2 mg/kg]), for their effects on sham and real drinking of 0.3 M NaCl. Sham drinking was markedly reduced by both antagonists whereas real drinking was unaffected. These effects did not appear to be due to malaise or suppression of motor behavior because drug-treated animals were able to increase ingestion substantially when offered less concentrated NaCl (0.1 M). These results suggest that the positive motivating properties of NaCl stimulation in depleted, sham-drinking rats are mediated by central D2 receptors.

A new taste reactivity analysis of the integration of taste and physiological state information.

We used conjoint manipulation of taste and physiological state to address the theoretical issue of signal integration. The interaction between taste (glucose concentration) and state (food deprivation) was evaluated using the taste reactivity method in which oral motor responses elicited by direct intraoral infusion are measured. The time frame of the typical taste reactivity paradigm, where observation is limited to the infusion period, was expanded to include the postinfusion interval. In each test session, rats received a series of trials consisting of 15-s intraoral infusions and 45-s postinfusion observation intervals. Two experiments were run in which glucose concentration was varied and rats were run nondeprived and after 24 h food deprivation. In experiment 1, glucose concentrations (0, 3.2, 6.25, 12.5, and 25%) were randomly presented during each test session. In experiment 2, individual glucose concentrations (0, 6.25, or 25%) were presented during separate sessions. For both, a deprivation condition was flanked by nondeprived (baseline) sessions. Concentration-response functions were comparable in both experiments. In each experiment, the shape of the concentration-response function was dramatically different during and after infusions. During infusions, there were no increases in glucose-elicited rhythmic oral responses beyond a very dilute concentration. After infusions, the concentration-response functions appeared linear across the concentration range. In both experiments, deprivation elevated responding only in the after-infusion periods. In experiment 1, the concentration-response function was uniformly elevated (on average, 27%) by deprivation, which if taken at face value would suggest an additive combination of taste and state feedback signals. In experiment 2, however, deprivation increased responding (approximately 30%) for 6.25%, but not for 0 or 25%, suggesting a stimulus specificity of the taste-state integration. Clearly then, the taste-state profiles differed as a function of experimental design. In the GENERAL DISCUSSION, we suggest that the uniform elevation of responding to all glucose concentrations, and to water, seen in experiment 1, may be an artifact of the random presentation of all stimuli during individual sessions. Experiment 2, in which stimuli were presented in a between-sessions design, may provide a truer reflection of the underlying integrative process.

c-Fos induction in rat brainstem in response to ethanol- and lithium chloride-induced conditioned taste aversions.

When consumption of a novel taste (conditioned stimulus; CS) is followed by exposure to a toxin, organisms will avoid consumption of that taste in the future. This learned response, known as a conditioned taste aversion (CTA), can be demonstrated using a variety of drugs, including lithium chloride (LiCl) and ethanol. c-Fos immunohistochemistry was used to examine neural activation in the rat brainstem associated with drug administration and with a CS taste previously paired with these drugs. Relative to saline controls, animals injected with either LiCl (76 mg/kg) or ethanol (3.5 g/kg) displayed greater c-Fos expression in area postrema, nucleus of the solitary tract (NTS), and lateral parabrachial nucleus. At these doses, LiCl- and ethanol-injected groups did not differ from each other. For establishing a CTA, intraoral infusion of a 0.15% saccharin solution was followed by injection of either LiCl or ethanol. Both LiCl and ethanol produced quantitatively similar CTAs. Relative to unpaired control groups, saccharin paired with either drug induced significant c-Fos expression in NTS. Thus, like LiCl, ethanol and tastes that have become aversive by virtue of their association with ethanol activate brainstem regions hypothesized to play a role in CTA learning.

Control of rubella in Israel: progress and challenge.

Despite a high-compliance school girl rubella immunization program since 1973 and a program for the immunization of women of childbearing age since 1980, sporadic cases of the congenital rubella syndrome (CRS) continue to occur in Israel, particularly following rubella epidemics. At highest risk for a child with CRS are unimmunized Arab women and immigrants from Ethiopia, although CRS has also occurred in infants of immunized non-immigrant women. In order to make progress towards the elimination of congenital rubella, the Israel Ministry of Health has incorporated into its rubella immunization program the intermediate goal of interrupting endemic rubella transmission in the country. To this end, universal rubella vaccination at age one began in 1989, a second dose at age six years was introduced in 1994, inclusion of boys in the program aimed at 12-year-olds began in late 1995, and catch-up campaigns to immunize never-immunized children, boys and girls, are planned. Moreover, women of childbearing age will be encouraged to receive a second dose of rubella vaccine. While the WHO goal of no indigenous CRS by the year 2000 will not be met, it is expected that in the coming decade substantial additional progress towards the elimination of CRS will be made.

Ingestive taste reactivity as licking behavior.

In ingestive taste reactivity analysis, the rhythmic oral motor responses observed during intraoral infusion of fluids normally ingested by rats are categorized and counted. These rhythmic movements can be likened to spout-licking in several respects. Both are emitted in the same frequency range (5-8 Hz), organized in a burst/pause pattern, and serve the function of intraoral transport of fluid into position for swallowing. The parallel suggests that a temporal pattern analysis, based on the spout-licking literature, can be fruitfully applied to the rhythmic movements that attend intraoral infusion. We provide a demonstration of such an analysis using an electromyographic (EMG) recording-based method for automated event detection. Eight rats received a 37.5% glucose solution (1.0 ml/min) in a series of 120 s infusion trials (45 s intertrial intervals) that was extended until the fluid was rejected. Movement counts declined 19.1% from the first to the last complete trial. Parameters derived from the pattern analysis (number of bursts, mean burst duration, pause durations, coefficient of variation for the distribution of within-burst intermovement intervals) were affected to a greater extent. The results indicate the potential value of temporal pattern analysis for various applications of the taste reactivity paradigm.

[Protection of medical personnel hands with Steriprest preparation]. / Zashchita ruk medpersonala s pomoshch'iu preparata "Steriprest".

A new ointment base "Amfilubre" is a chemically bound copolymer of hydrophobic silicone and hydrophylic polyethylene glycol. That provides tight adhesion of the composition to the skin and effective intramolecular incorporation of variable substances. When polyformaldehyde is dispersed in "Amfilubre", the obtained preparation "Steriprest" enables momentary sterilization of skin and instruments due to discharge of the disinfectant from the protective covering layer. The process lasts for several hours, leading to longer protection time.